Nucleoside is a glucoside formed by the condensation of purine and pyrimidine bases with a cyclic ribose or deoxyribose. The saccharide is linked with bases through glucoside bonds, that is, the carbon atom at position 1 (C1) of the ribose or deoxyribose is linked with the nitrogen atom at position 1 (N1) of the pyrimidine base or the nitrogen atom at position 9 (N9) of the purine base. The saccharide has both α- and β-configurations, as C1 in the saccharide ring is an asymmetrical carbon atom.
Native nucleosides are all in β configuration, which are key ingredients constituting the life macromolecule RNA and DNA, are native metabolism activators, directly enter the cells to participate in the saccharide metabolism and promote the synthesis of proteins, promote the morbid cells and tissues to restore their normal physiological functions. Modified and engineered nucleoside compounds, the structures of which were very similar to that of native nucleoside, have currently been considered as the chemotherapeutic agents with the greatest potential, with good activities of anti-viral, anti-tumor, immunomodulation or anti-bacterial, etc. For example, the known nucleoside antitumor drugs include Decitabine, Gemcitabine, Azacitidine, Capecitabine, Fludarabine or the like. The known nucleoside anti-viral drugs include Lamivudine, Zidovudine, Telbivudine, Entecavir, Emtricitabine, Fomivirsen or the like.
In recent years, the development of nucleoside analogues with low toxicity, high anti-tumor and anti-viral activities has become the study focus, especially the single enantiomer in β-configuration has received widespread attention. As nucleoside analogues in β-configuration have better similarity with native nucleosides, it has been the technical difficulty that needs to be resolved and improved on how to synthesize nucleoside analogues in β-configuration stereoselectively with a more economical process.
Take decitabine for example, the drug is a 2′-deoxycytidine analogue developed by SuperGen Co., USA, marketed first in USA in 2006, useful for treating myelodysplastic syndrome in clinic. Currently, there are two main synthetic methods:
Method 1 (U.S. Pat. No. 3,350,388; J. Org. Chem., 1974, 39, 3672-3674): Intermediate 2′ was prepared with 3,5-di-O-p-toluene formyl-1,2-deoxy-β-D-arabinofuranosyl isocyanate and S-methyl isothiourea as the raw materials, which was then reacted with triorthoformate through a cyclization reaction to give 1-(3,5-di-O-p-toluene formyl-1,2-deoxy-β-D-arabinofuranosyl)-4-methyl-2-mercapto-2-oxo-1,2-dihydro-1,3,5-triazine (intermediate 3′), which was reacted with ammonia/methanol to give the intermediate 4′, and finally deprotected by sodium methoxide/methanol to give Decitabine. Its synthesis route was as follows:

This route was complex in design, used many chemical reagents, and cumbersome in operation, not meeting the production requirement of low consumption and high efficiency.
Method 2 (Nucl Acid Res, 1978, s4, 109-113): Silyl ether B was prepared at reflux with 5-azacytosine A as the raw material and with hexamethyldisilazane (HMDS) as the silyl etherification reagent and the solvent, which was then condensed with chlorinated deoxyribose C under the catalysis of trimethylsilyl trifluoromethanesulfonate (TMSOTf) to give the intermediate D, which was then deprotected by sodium methoxide/methanol to give Decitabine. Its synthesis route was as follows:

This route is the most common route in the industrial production of decitabine currently, in which the reaction steps are less than those in method 1, but there remains many problems: 1) HMDS was used heavily as the solvent, a large amount of ammonia was produced during the preparation of silyl ether 2, polluting the production environment seriously; 2) the excess amount of HMDS has to be removed from the reaction liquid through concentration, until a pasty mixture difficult to stir was obtained, the residue of which tend to cure during the concentration, easily causing the stirring system to be operated irregularly or be broken, not applicable for the production on the industrial level; 3) HMDS was difficult to be removed absolutely, which remains in silyl ether B and leads to the severe reduction of the β/α proportion of the intermediate D during the synthesis of the intermediate D, and very low yield of materials in β configuration.
Currently, the synthesis of other nucleoside drugs also generally use HMDS as the silylating agent to protect the active hydrogen on the base, the synthesis route or its path was substantially the same as the above route 2, and there remains the same technical problems.
Therefore, effective methods for producing β-nucleoside compounds remain to be insufficient in the prior art, it has become an urgent problem to be solved on the general stereoselective synthesis of the bioactive β-nucleoside compounds.